Macromonomers for preparation of degradable polymers and model networks

ABSTRACT

The present invention relates to methods for preparing degradable model networks from any monomer functionality with any degradation methodology. It is based on the use of Atom-Transfer Radical Polymerization and CLICK chemistry to form the desired product.

RELATED APPLICATIONS

The present application is a continuation of U.S. application Ser. No.12/363,343 filed Jan. 30, 2009 which is a continuation of InternationalApplication PCT/US/06/041270 filed Oct 24, 2006 which claims priority toU.S. Provisional Application Ser. No. 60/834,501 filed on Aug. 1, 2006,the contents of which are incorporated herein in their entirety.

GRANT INFORMATION

This invention was made with government support under Grant Nos.DGE-02-21589, DMR-02-13574, DMR-02-14363, and CHE-04-15516 awarded bythe National Science Foundation and Grant No. DAAD19-06-0104 awarded bythe U.S. Army Research Office. The government has certain rights in theinvention.

1. INTRODUCTION

The present invention relates to macromonomers suitable for preparingdegradable polymers and model networks, methods for their production,and polymers and polymeric articles fabricated therefrom.

2. BACKGROUND OF THE INVENTION

2.1. Polymer Networks

Synthetic polymer networks have been the subject of extensivetheoretical, physical, and chemical study over the past century (i,ii),and are still finding new applications. (iii,iv). The structurallysimplest polymer networks are termed “model networks” (MNs) and aretypically comprised of linear telechelic, or α,ω-functional, polymers,or macromonomers (MAC), covalently crosslinked through their end groupswith multi-functional small molecules. Macromonomers are defined asoligomers with a number average molecular weight M_(n) between about1,000 and about 10,000 that contain at least one functional groupsuitable for further polymerizations. MNs are unique because thecrosslink functionality is constant and predetermined, so that themolecular weight between crosslinks is defined by that of the MAC, andthe material is homogenous with respect to the crosslink density. (v).Well defined-pore sizes are therefore obtained, providing potentialadvantages for certain applications. (vi). Although MNs havewell-defined structure, they are not considered ‘ideal’ in a theoreticalsense, because they unavoidably contain some number of unreactedfunctionalities, dangling chains, chain entanglements, and inelasticloops. (v).

Due to their insolubility in all solvents, MNs are notoriously difficultto characterize by common chemical techniques. As a consequence, certainnetwork parameters, like the number of dangling chains, are typicallyestimated from combining macroscopic measurements (swelling, rheology,etc. . . . ) with theory. Recent research has utilized a hydrolyticallylabile crosslinker for the degradation of cross-linked star-polymermodel networks (CSPMNs), and size exclusion chromatography (SEC) of thedegradation products to verify the parent network structure. (iii).However, such CSPMNs have been prepared successfully only through theuse of methyl methacrylate (MMA) monomers. If applied to networks oflinear MACs, analysis of degradation products can also, in principle,yield the number of dangling chains after subtracting out the solportion.

Recently, the development of a controlled/“living” free radicalpolymerization technique known as Atom Transfer Radical Polymerization(ATRP), described in Wang, J-S, and Matyjaszewski, K., Journal of theAmerican Chemical Society, Vol, 117 (1995), p. 5641, has renderedpossible the synthesis of a variety of well-defined polymers with lowpolydispersity indexes (M_(w)/M_(n), <13, where M_(w), is the weightaverage molecular weight) and predetermined molecular weights, definedby the relationship DP=Δ[M]/[I]₀, where DP is the degree ofpolymerization, [M] is the reacted monomer concentration, and [I]₀ isthe initial concentration of the initiator. The mechanism of ATRP, shownin Scheme 1 below, is believed to be based on the repetitive addition ofa monomer M to growing radicals R• generated from alkyl halides R—X by areversible redox process. This process is catalyzed by transition metalcompounds, especially cuprous (Cu(I)) halides, complexed by suitableligands such as bipyridines and bi-, tri- and tetradentate amines, asdescribed in Xia, J. Zhang, X. and Matyjaszewski, K., American ChemicalSociety Symposium Series, Vol. 760 (2000), pp. 207-23. The rate ofmonomer addition is dependent on the equilibrium constant between theactivated (Cu(I)) and deactivated (Cu(II)) species. By maintaining a lowconcentration of active radicals, slow growth of the molecular weight ispromoted and the “living” ATRP process is controlled. The degree ofpolymerization is determined by the ratio of reacted monomerconcentration to initiator concentration (DP_(n)=Δ[M]/[R—X]₀).

Radical reactions allow for polymerization of a large variety of vinylmonomers and are tolerant to many functional groups. ATRP is applicableto the reactions of hydrophobic monomers such as acrylates,methacrylates and styrene, as shown in Patten, T, E. and Matyjaszewski,K. Advanced Materials, Vol. 10 (1998), pp. 901-915, and also ofhydrophobic and functional monomers such as 2-hydroxyethyl acrylate,2-hydroxyethyl methacrylate, 2-(dimethylamino)ethyl methacrylate(DMAEMA) and 4-vinylpyridine. See Matyjaszewski, K., Gaynor, S. G., Qiu,J., Beers, K., Coca, S., Davis, K., Muhlebach, A., Xia, J., and Zhang,X., American Chemical Society, Symposium Series, Vol. 765 (2000), pp.52-71.

Further, researchers have recently reported the copper (I) catalyzedazide-alkyne cycloaddition (CuAAC) reaction (vii, viii), which hasemerged as the best example of “click chemistry,” (ix) characterized byextraordinary reliability and functional group tolerance. This ligationprocess has proven useful for the synthesis of model polymers andmaterials in many situations.

2.2. Degradable Polymers

A degradable polymer is a polymer that contains a cleavage site, a bondin the chemical structure that will cleave under certain conditions.Degradable polymers have many applications, such as drug delivery,medical devices, environmentally-friendly plastics, and temporaryadhesives or coatings. A variety of natural and synthetic polymers aredegradable. Generally, a polymer based on a C—C backbone tends to benon-degradable, while heteroatom-containing polymer backbones aredegradable. Degradability can therefore be engineered into polymers bythe addition of chemical linkages such as anhydride, ester, or amidebonds, among others.

Biodegradable polymers with hydrolyzable chemical bonds have been thesubject of extensive research. Polymers based on polylactide (PLA),polyglycolide (PGA), polycaprolactone (PCL) and their copolymers havebeen extensively employed as biodegradable materials. Degradation ofthese materials yields the corresponding hydroxyacids, making them safefor in vivo use.

Photodegradable polymers can be created by the addition ofphotosensitive groups (promoters) to the polymer. Two common promotersare carbonyl groups and metal complexes, which cleave when exposed tosufficient ultraviolet radiation, such as that present in sunlight.However, metals left behind by cleavage of these heavy metal complexescan cause environmental problems in sufficient quantities.

Degradable model networks in particular have many potentialapplications, yet in order to be successfully used, a method of yieldingMACs of low polydispersity that possess orthogonal crosslinking andvarious degradation functionalities is necessary.

3. SUMMARY OF THE INVENTION

The present invention relates to macromonomers suitable for preparingdegradable polymers and model networks, methods for their production,and polymers and polymeric articles fabricated therefrom. It is based,at least in part, on the discovery that ATRP can be used to synthesizemacromonomers of low polydispersity that possess orthogonalcross-linking and degradation functionalities. Such macromonomersinclude, in non-limiting embodiments, both α,ω-difunctional andheterobifunctional macromonomers, and star polymer macromonomers, all ofwhich are preferably rendered degradable through the incorporation ofvarious degradation functionalities as taught by the inventive method.

The present invention further provides for a wide variety of articlesfabricated from materials comprising the macromonomers of the invention,including polymer model networks, hydrogels, drug delivery vehicles,tissue scaffolding, cosmetics, bags, films, surface modification agents,contrast agents, and nanoparticles.

4. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Schematic of α,ω-Difunctional Macromonomer Synthesis.

FIG. 2. Schematic of Heterobifunctional Macromonomer Synthesis.

FIG. 3. Schematic of Star Polymer Macromonomer Synthesis.

FIG. 4. Schematic of ozonolyzable Model Network synthesis anddegradation.

FIG. 5. Hypothesized Molecular structure of ozonolyzable Model Network,MAC, and degradation products.

FIG. 6. IR spectra of (from top to bottom) α,ω-bromo-poly(tert-butylacrylate), 1, control crosslinking reaction without copper, 1:1azide:alkyne MN, and 2:1 azide:alkyne MN in the azide stretch region(˜2100 cm⁻¹).

FIG. 7. SEC chromatograms of MAC 1 before and after ozonolysis and theozonolysis products of MNs 1a and 1b.

FIG. 8. SEC chromatograms of MAC 2, MAC 2 after photocleavage, anddegradation product 4.

FIG. 9. Hypothesized Molecular structure of photodegradable ModelNetwork, and resulting degradation product.

FIG. 10. Schematic of photodegradable Model Network synthesis from starpolymer macromonomers and degradation.

FIG. 11. ¹H NMR resonances of MAC 17.

FIG. 12. FTIR spectra of 4-arm ptBA star polymer 15 and MAC 17.

5. DETAILED DESCRIPTION OF THE INVENTION

For clarity, and not by way of limitation, the detailed description ofthe invention is divided into the following subsections:

(5.1) Difunctional Macromonomer Synthesis;

(5.2) Heterobifunctional Macromonomer Synthesis;

(5.3) Star Polymer Macromonomer Synthesis;

(5.4) Uses of the Invention

5.1 α,ω-Difunctional Macromonomer Synthesis

In one set of embodiments, the present invention provides for a methodof synthesizing α,ω-difunctional macromonomers with a general structureof C—(R)_(n)-L-(R)_(n)—C and α,ω-difunctional block macromonomers with ageneral structure of C—(R′)_(n)—(R)_(n)-L-(R)_(n)—(R′)_(n)—C. “L” is alinker, chosen from the group consisting of non-degradable,photodegradable, ozonolyzable, biodegradable, or hydrolyzable. “R” is amonomer, selected from the group consisting of acrylates, methacrylates,styrenics, and polyacids. “R′” is a monomer, different from “R,”selected from the group consisting of acrylates, methacrylates,styrenics, and polyacids. “n” is a variable representing the number ofmonomers in the macromonomer, and is chosen such that the macromonomerhas a molecular weight between about 1,000 and 10,000. “C” is a terminalfunctional group, chosen from the group consisting of hydroxyl, allyl,acrylate, or azide.

As shown in FIG. 1, synthesis begins with a bifunctional polymerizationinitiator (10) containing a linker “L” (20), represented as a circle.The linker “L” (20) may be non-degradable, but may also includephotodegradable, ozonolyzable, biodegradable or hydrolyzable linkages.As examples, an ozonolyzable linker may include an olefin moiety, whilea photodegradable linker may include a nitrobenzylcarbonyl moiety. Abiodegradable linker may include a peptide bond, while hydrolyzablelinkers may include ester linkages.

The initiator (10) is bifunctional, containing terminal halogen groups(120) as initiation sites for polymerization. Bromine is especiallysuited for such use as an initiation site for ATRP reactions. Specific,non-limiting examples of initiator (10) are1,2-bis(bromoisobutyryloxy)-2-butene (Compound 4) described in Section 6below, and the novel bifunctional nitrobenzyloxycarbonyl (NBOC)initiator (1) described in Section 7 below.

The initiator (10) is then reacted with a sufficient amount of a chosenmonomer “R” (30) through ATRP to form a macromonomer (40), an oligomerwith a number average molecular weight M_(N) between about 1,000 andabout 10,000. The monomer “W” (30) can include acrylates, methacrylates,styrenics, and polyacids. However, due to ATRP's sensitivity to thepresence of acid functionalities, in order to polymerize polyacidmonomers, monomers with protected acid groups must be polymerizedfollowed by a deprotection step to regenerate the desired acidfunctionality. If an α,ω-difunctional block macromonomer (110 or 105) isdesired, the ATRP step is repeated using a different monomer base “R′”(90), such that the resulting oligomer has a M_(N) between about 1,000and about 10,000. The resulting macromonomers (100) and (40) arepolymeric halides, A specific, non-limiting example of macromonomer (40)is α,ω-bromo-poly(tert-butyl acrylate) (Compound 5), described inSection 6 below.

The description will be continued now with respect to synthesis of anα,ω-difunctional macromonomer (50 or 70). Synthesis of anα,ω-difunctional block macromonomer is conducted using similar steps. Inorder to continue synthesis, the terminal halogen groups of theresulting polymeric halide (40) can be converted via apost-polymerization transformation (PPT) to a hydroxyl, allyl, acrylate,or azide functional group “C” (60), represented as an octagon, formingan α,ω-difunctional macromonomer (50). Hydroxyl groups may be added bytreating the halide (40) with 4-aminobutanol in dimethylformamide (DMF),while allyl groups may be added by treating the halide (40) withallyltributyltin. Azide groups are especially suited for the CuAAC“click chemistry” reaction, and may be added by treating the halide (40)with sodium azide in DMF. Following addition of a terminal azide group,further terminal functional groups (80), represented as triangles, maybe added, including aldehyde, hydroxy, carboxy, amine, peptide, epoxide,or thiol groups, through click reactions of the resulting terminal azide(60) with functional alkyne, norbornadiene, or cyclooctyne. Use of afunctional alkyne requires a copper catalyst, while use of a functionalcyclooctyne does not require a copper catalyst and is thus better suitedfor biomedical applications. The ability to add various terminalfunctional groups allows the user to choose the cure chemistry that maybe utilized later to crosslink the linear macromonomers to form apolymer MN. Specific non-limiting examples of such polymer MNs that maybe formed are MNs 1a, 1b, and 3, described in Sections 6 and 7 below.Specific non-limiting examples of crosslinkers that may be used are CLaand CLb, described in Section 6 below. If the click chemistry process ischosen for crosslinking, subsequent to crosslinking, unreacted terminalazide groups may also be replaced with similar terminal functionalgroups. Specific, non-limiting examples of α,ω-difunctional macromonomer(50) are MAC 1, described in Section 6 below, and MAC 2, described inSection 7 below,

5.2 Heterobifunctional Macromonomer Synthesis

In further non-limiting embodiments, the present invention provides fora method of synthesizing Heterobifunctional Macromonomers with a generalstructure of E-L-(R)_(n)—C and Heterobifunctional Block Macromonomerswith a general structure of E-L-(R)—(R′)_(n)—C. “E” is a terminalfunctional group, chosen from the group consisting of hydroxyl, allyl,acrylate, or alkyne. “L” is a linker, chosen from the group consistingof non-degradable, photodegradable, ozonolyzable, biodegradable, orhydrolyzable. “R” is a monomer, selected from the group consisting ofacrylates, methacrylates, styrenics, and polyacids. “R′” is a monomer,different from “R,” selected from the group consisting of acrylates,methacrylates, styrenics, and polyacids. “n” is a variable representingthe number of monomers in the macromonomer, and is chosen such that themacromonomer has a molecular weight between about 1,000 and 10,000. “C”is a terminal functional group, chosen from the group consisting ofhydroxyl, allyl, acrylate, or azide.

As shown in FIG. 2, synthesis begins with a heterobifunctionalpolymerization initiator (230) containing a linker “L” (200),represented as a circle. Linker “L” (200) may be non-degradable, but mayalso include photodegradable, ozonolyzable, biodegradable, orhydrolyzable linkages. As examples, an ozonolyzable linker may includean olefin moiety, while a photodegradable linker may include anitrobenzylcarbonyl moiety. A biodegradable linker may include a peptidebond, while hydrolyzable linkers may include ester linkages.

The initiator (230) is heterobifunctional, containing one terminalhalogen group (220) as an initiation site for polymerization, and afunctional end group “E” (210) that may be a hydroxyl, allyl, acrylate,or alkyne group. Bromine is especially suited for such use as aninitiation site for ATRP reactions.

The initiator (230) is then reacted with a chosen monomer “R” (240)through ATRP to form a macromonomer (250), an oligomer with a numberaverage molecular weight M_(N) between about 1,000 and about 10,000. Themonomer “R” (240) can include acrylates, methacrylates, styrenics, andpolyacids. However, due to ATRP's sensitivity to the presence of acidfunctionalities, in order to polymerize polyacid monomers, monomers withprotected acid groups must be polymerized followed by a deprotectionstep to regenerate the desired acid functionality. If aheterobifunctional block macromonomer (295 or 292) is desired, the ATRPstep is repeated using a different monomer base, “R′” (265), such thatthe resulting oligomer has a M_(N) between about 1,000 and about 10,000.The resulting macromonomers (275) and (250) are polymeric halides thatcontain terminal halogen groups (255) and (285) at the end of a polymerchain on one end of the linkage (200), and the original functional group(210) on the other end.

The description will be continued now with respect to synthesis of aheterobifunctional macromonomer (260 or 280). Synthesis of aheterobifunctional block macromonomer is conducted using similar steps.In order to continue synthesis, the terminal halogen group (255) of theresulting polymeric halide (250) can be converted via apost-polymerization transformation (PPT) to a hydroxyl, allyl, acrylate,or azide functional group “C” (270), represented as an octagon, forminga heterobifunctional macromonomer (260). Hydroxyl groups may be added bytreating the halide (250) with 4-aminobutanol in DMF, while allyl groupsmay be added by treating the halide (250) with allyltributyltin. Azidegroups are especially suited for the CuAAC “click chemistry” reaction,and may be added by treating the halide (250) with sodium azide in DMF.Following addition of a terminal azide group, a further terminalfunctional end group (290), represented as a triangle, may be added,including aldehyde, hydroxy, carboxy, amine, peptide, epoxide, or thiolgroups through click reactions of the resulting terminal azide withfunctional alkyne, norbornadiene, or cyclooctyne. Use of a functionalalkyne requires a copper catalyst, while use of a functional cyclooctynedoes not require a copper catalyst and is thus better suited forbiomedical applications. The ability to add various terminal functionalgroups allows the user to choose the cure chemistry that may be utilizedlater to crosslink the linear macromonomers to form a polymer MN.Specific non-limiting examples of crosslinkers that may be used arecrosslinkers CLa and CLb, described in Section 6 below. If the clickchemistry process is chosen for crosslinking, subsequent tocrosslinking, unreacted terminal azide groups may also be replaced withsimilar terminal functional groups.

5.3 Star Polymer Macromonomer Synthesis

In one set of embodiments, the present invention provides for a methodof synthesizing star polymer macromonomers with a general structure of:

and star polymer block macromonomers with a general structure of:

“L” is a linker, chosen from the group consisting of non-degradable,photodegradable, ozonolyzable, biodegradable, or hydrolyzable. “R” is amonomer, selected from the group consisting of acrylates, methacrylates,styrenics, and polyacids, “R′” is a monomer, different from “R,”selected from the group consisting of acrylates, methacrylates,styrenics, and polyacids. “n” is a variable representing the number ofmonomers in the macromonomer, and is chosen such that the macromonomerhas a molecular weight between about 4,000 and 40,000. “C” is a terminalfunctional group, chosen from the group consisting of hydroxyl, allyl,acrylate, or azide.

As shown in FIG. 9, synthesis begins with a tetrafunctionalpolymerization initiator (310) containing a linker “L” (320),represented as a circle, for each initiation site. The linker “L” (320)may be non-degradable, but may also include photodegradable,ozonolyzable, biodegradable or hydrolyzable linkages. As examples, anozonolyzable linker may include an olefin moiety, while aphotodegradable linker may include a nitrobenzylcarbonyl moiety. Abiodegradable linker may include a peptide bond, while hydrolyzablelinkers may include ester linkages.

The initiator (310) is tetrafunctional, containing four terminal halogengroups (325) as initiation sites for polymerization. Bromine isespecially suited for such use as an initiation site for ATRP reactions.

The initiator (310) is then reacted with a sufficient amount of a chosenmonomer “R” (330) through ATRP to form a star polymer macromonomer(340), an oligomer with a number average molecular weight M_(N) betweenabout 1,000 and about 10,000. The monomer “R” (330) can includeacrylates, methacrylates, styrenics, and polyacids. However, due toATRP's sensitivity to the presence of acid functionalities, in order topolymerize polyacid monomers, monomers with protected acid groups mustbe polymerized followed by a deprotection step to regenerate the desiredacid functionality. If a star polymer block macromonomer (355 or 395) isdesired, the ATRP step is repeated using a different monomer base “R′”(390), such that the resulting oligomer has a M between about 4,000 andabout 40,000. The resulting star polymer macromonomers (340) and (345)are polymeric halides. A specific, non-limiting example of macromonomer(340) is ptBA star polymer 15, described in Section 7b below.

The description will be continued now with respect to synthesis of astar polymer macromonomer (350 or 370). Synthesis of a star polymerblock macromonomer is conducted using similar steps. In order tocontinue synthesis, the terminal halogen groups of the resultingpolymeric halide (340) can be converted via a post-polymerizationtransformation (PPT) to hydroxyl, allyl, acrylate, or azide functionalgroups “C” (360), represented as octagons, forming a star polymermacromonomer (350). Hydroxyl groups may be added by treating the halide(340) with 4-aminobutanol in dimethylformamide (DMF), while allyl groupsmay be added by treating the halide (340) with allyltributyltin. Azidegroups are especially suited for the CuAAC “click chemistry” reaction,and may be added by treating the halide (340) with sodium azide in DMF.Following addition of a terminal azide group, further terminalfunctional groups (380), represented as triangles, may be added,including aldehyde, hydroxy, carboxy, amine, peptide, epoxide, or thiolgroups, through click reactions of the resulting terminal azide (360)with functional alkyne, norbornadiene, or cyclooctyne. Use of afunctional alkyne requires a copper catalyst, while use of a functionalcyclooctyne does not require a copper catalyst and is thus better suitedfor biomedical applications. The ability to add various terminalfunctional groups allows the user to choose the cure chemistry that maybe utilized later to crosslink the star polymer macromonomers to form apolymer MN. A specific non-limiting example of such polymer MNs that maybe formed is MN 19, described in Section 7b below. A specificnon-limiting example of a crosslinker that may be used is Compound 18,described in Section 7b below. If the click chemistry process is chosenfor crosslinking, subsequent to crosslinking, unreacted terminal azidegroups may also be replaced with similar terminal functional groups. Aspecific, non-limiting example of star polymer macromonomer (350) is MAC17, described in Section 7b below.

5.4 Uses of the Invention

The macromonomers of the present invention may be used to producecross-linked polymer model networks, gels, and hydrogels.Hydroxy-terminated macromonomers allow use of a polyurethane cure, whileamine-terminated macromonomers allow an epoxide/polyurethane cure.Alkene-terminated macromonomers allow a free-radical/hydrosilylationcure, while epoxide-terminated macromonomers allow an amine cure, andthiol-terminated macromonomers allow a disulfide/vulcanization cure.Alkyne-terminated macromonomers allow a hydrosilylation/azide cure,while azide-terminated macromonomers allow an alkyne/Diels-Alder cure.The ability to select the cure chemistry desired allows the user totailor such macromonomers to their expected environment. Such materialshave a broad range of applications, including cosmetics such as nailpolish, biomedical products such as degradable hydrogels or tissuescaffolding, consumer products such as degradable bags or films, andpharmaceutical products such as drug delivery vehicles. Macromonomersare also useful as surface modification agents, contrast agents, andnanoparticles.

6. EXAMPLE—PREPARATION AND DEGRADATION OF OZONOLYZABLE MODEL NETWORK

General

With reference to FIG. 4, this scheme was employed to prepare the firsttert-butyl acrylate based MNs (1a, 1b) (430) comprised of anα,ω-azido-poly(tBA) MAC (1) (400) crosslinked with tri- (410) and tetra-(not shown) acetylene crosslinkers (a and b respectively). Aftersynthesis, the olefin moiety (420) at the center of the MAC (400) wascleaved through ozonolysis to form tri-armed polymers (440) withaldehyde terminal groups (450).

All reagents were purchased from Aldrich chemical company and were usedas supplied unless otherwise noted. Tert-butyl acrylate was distilledunder reduced pressure over Call prior to use. Toluene andN,N,N′,N″,N″-pentamethyldiethylenetriamine (PMDETA) were degassed withargon for 20 m prior to use. Crosslinkers2,2,2-tris(2-propynyloxymethyl)ethanol (CLa) andtetrakis(2-propynyloxymethyl)methane (CLb) were prepared according toliterature procedures. (x, xi, xii). SEC measurements were performed ona Knauer GPC system with a Knauer K-2301 refractive index detector and aSpark Holland Basic Marathon autosampler. Three Polymer Laboratories 5μm particle size PLgel columns (one 100 Å and two MIXED-D pore types)placed in series were employed for the chromatography. The system wascalibrated against linear polystyrene standards ranging in molecularweight from 580-377,400 Da. Experiments were performed at roomtemperature in THF eluant with a flow rate of 1.0 mL/min. Ozone fordegradation studies was generated from an Ozone Lab OL100 OzoneGenerator.

Synthesis of 1,2-bis(bromoisobutyryloxy)-2-butene (Compound 4)

Triethylamine (1.20 g, 11.8 mmol) was added to a round-bottom flaskcontaining 2-butene-1,4-diol (0.454 g, 5.15 mmol) and tetrahydrofuran(THF, 30 mL). This solution was added dropwise to a stirring solution ofα-bromoisobutyryl bromide (2.60 g, 1.40 mL) in THF (25 mL) at 0° C. Awhite precipitate formed immediately. The mixture was stirred for 2 h at0° C. followed by overnight stirring at room temperature. After thistime, the reaction mixture was filtered, condensed on a rotaryevaporator, diluted with ethyl acetate (EtOAc, 50 mL), and extracted 4times with water (50 mL). The organic layer was dried over MgSO₄,filtered, condensed on a rotary evaporator, and dried en vacuo overnightto yield 1,2-bis(bromoisobutrylyoxy)-2-butene (1.68 g, 85%) as a yellowoil.

Synthesis of ozonolyzable α,ω-bromo-poly(tert-butyl acrylate) (Compound5)

CuBr (418 mg, 2.91 mmol) and Compound 4 (565 mg, 1.46 mmol) were addedto a clean, dry round bottom flask, which was subsequently evacuated for15 m and back-filled with argon. Freshly distilled tert-butyl acrylate(15.0 g, 117 mmol) was added via a degassed syringe followed by degassedtoluene (7.5 mL), and PMDETA (489 mg, 2.93 mmol). The reaction flask wasimmediately submerged in liquid N₂ until frozen, evacuated for 15 m,removed from liquid N₂, and backfilled with argon. When the mixturethawed completely, the flask was submerged in a 70° C. oil bath andstirred for 1 h under argon atmosphere. After 1 h, the reaction flaskwas opened to air, and the viscous, black mixture was diluted withtetrahydrofuran (20 mL) and frozen in liquid N₂. After thawing, themixture was passed through a column of neutral alumina, concentrated ona rotary evaporator, precipitated in a 10:1 volume of 50-50methanol-water three times, dissolved in diethyl ether, dried overMgSO₄, filtered, concentrated on a rotary evaporator, and dried in vacuofor 2 d to yield compound I (6.90 g, M_(n)(NMR): 10,600 Da) as a whitesolid.

Synthesis of MAC 1

Sodium azide (57.5 mg, 884 mmol) was added to a round-bottom flaskcontaining Compound 5 (3.4 g, 0.402 mmol) dissolved in DMF (100 mL). Thereaction mixture was stirred at 50° C. for 1d after which time it wasallowed to cool to room temperature, diluted with ether (50 mL), andextracted 4 times with water (100 mL). The organics were concentrated ona rotary evaporator and precipitated into a 10:1 volume of 50-50methanol-water. After decanting the methanol-water solution, theremaining solid was dissolved in diethyl ether, dried over MgSO₄,filtered, concentrated on a rotary evaporator, and dried for 2 d invacuo to yield MAC 1 (3.06 g, 90%) as a white solid. The success of thesubstitution reaction was indicated by the shift of the H NMR resonanceof the proton next to the end groups, the appearance of a strongabsorbance in the IR spectrum characteristic of alkyl azide, and byelemental analysis, the latter showing the transformation to be complete

Typical Procedure for the Crosslinking MACs with CLs to Form MNs 1a and1b Through CLICK Chemistry

Crosslinkers CLa (410 and 510) and CLb (not Shown in Figures)

MAC 1 (3/2 or 2 equiv. depending on CLa or CLb respectively) was addedto a clean vial followed by the copper catalyst (CuBr, Cui, CuSO₄, orCuBr(PPh₃)₃, 10 equiv. to alkyne). The vial was evacuated for 5 minutesand backfilled with argon before degassed solvent (DMF or toluene, 0.5mL/g of MAC) was added. Sodium ascorbate (4 M in H₂O, 20 equiv.) andalkyl amine (PMDETA or DIEA, 10 equiv.) were then added if necessary.The vial was immediately placed in an oven preset to 800° C. and allowedto react for the required time. In most cases) insoluble materialformed. However, the appearance of the materials varied from insolubleparticulates to stable homogeneous gels depending on the reactionconditions. When the term “homogeneous” is used, it implies that thematerial was uniform in appearance and that the entire reaction mixtureformed a single material. Also, the homogenous materials weremechanically stable, meaning they were able to be handled withoutbreaking apart. When aqueous sodium ascorbate was added to the reactionmixture, a precipitate would form in the region where the watercontacted the DMF solution containing MAC 1. These materials arereferred to as “slightly more heterogeneous” because at the end of thecrosslinking reaction, this region would have a rougher texture.“Heterogeneous” also refers to cases where the reaction mixture formedanything but a single gel (e.g. particulates). In general, thesolvent-swollen “heterogeneous” materials would break apart under theirown weight. Due to copper catalyst trapped within the networks, all ofthe materials were colored after the crosslinking reaction, but repeatedswelling in fresh acetone yielded colorless materials.

As shown in FIG. 6, the IR spectra of the products (630) closelyresembled that of MAC 1 (610) without the azide peak, indicating thatthe crosslinking proceeded in high yield. For comparison, the spectrumof α,ω-bromo-poly(tert-butyl acrylate) is indicated (600). When nocopper catalyst was employed (620), the azide remained, and when a 2:1ratio of azide to alkyne was used (640), the resulting material stillpossessed azide functionalities, which could presumably be used forpost-crosslinking functionalization of the material. The olefin moietycan also be functionalized after crosslinking, providing another meansof tailoring the properties of these materials.

Ozonolysis of MAC 1, MNs 1a and 1b

In order to determine the approximate amount of unreacted material leftafter CuAAC crosslinking and to confirm that the M_(n) betweencrosslinks was well-defined, MNs 1a and 1b were ozonolyzed to yieldsoluble products. The substrate was dissolved (MAC 1) or swollen (MNs 1aand 1b) in CH₂Cl₂ (20 mL) in a glass vial. The vial was submerged in anacetone/dry ice bath at −76° C. and allowed to cool for 5 m. O₃ wasbubbled directly into the system via a glass Pasteur pipette for 20 muntil the solution became blue and there were no insoluble materials.After this time, the solution was allowed to warm to room temperature,dried on a rotary evaporator, dissolved in THF, passed through a shortalumina plug, and analyzed by SEC.

As shown in FIG. 5, based on the hypothesized network structure for MN1a (520) (using tri-functional crosslinks (510)), ozonolysis of theolefin moiety present at the midpoints of each junction can yield onlyfour products (530-560) the major of which is a three-armed star polymer(530) with M equaling 1.5 times that of MAC 1 (500).

With reference to the SEC chromatograph shown in FIG. 7, it can be seenthat the major degradation product of MN 1a had the expected molecularweight. The ozonolysis product from MAC 1 (730) had a M, approximatelyone-half that of MAC 1 (720). Similarly, the major degradation productof MN 1a (710) had an M_(n) approximately equal to twice that of MAC 1,which would be expected for a tetrafunctional MN. However, both networksalso possess a peak corresponding to one-half the M_(n) of MAC 1 (720).Considering that no extraction of soluble material was performed beforeozonolysis, this peak must arise from cases in which only one, orneither, of the MAC azides reacted. The sample from MN 1b (700) showedmore of this unreacted material, suggesting that the increased sterichindrance of a tetrafunctional network may limit the extent ofcrosslinking.

7. EXAMPLES OF PREPARATION AND DEGRADATION OF PHOTODEGRADABLE MODELNETWORK

a. Linear Macromonomer

The procedure described in above section 5.1 was adapted for thepreparation of photodegradable tBA MNs by ATRP synthesis of aphotocleavable tBA macromonomer (MAC) from a novel bifunctionalnitrobenzyloxycarbonyl (NBOC) initiator (1). SEC characterization of theMN photodegradation products provides evidence that the pore sizes ofthe parent MN were defined by the number average molecular weight(M_(a)) of the MAC.

Synthesis of MAC 2

The preparation begins with synthesis of the NBOC-ATRP initiator 1,which is capable of photocleavage via the well-known Norrish type IImechanism. (xiii).

ATRP of tBA from 1 proceeded in a controlled fashion to yieldα,ω-bromo-poly(tBA) (ptBA, M_(n)=10,400, PDI=1.16). Treatment of thispolymer with sodium azide in DMF yielded MAC 2.

Photocleavage of 2 proceeds quantitatively to yield linear polymers withnumber average molecular weight (M_(n)) one-half that of 2.

Crosslinking of 2 to Form MNs

Crosslinking of 2 with a tetra-functional acetylene via CuAAC yieldedmodel network 3. The most homogeneous materials formed when CuBr wasused as the CuAAC catalyst, in the presence of 2,2′-bipyridyl ligand,and DMF solvent under argon atmosphere. Ultrasonication of this mixturefor 15 seconds yielded a viscous solution which was subsequently curedovernight at 40° C. After this time, the materials were repeatedlyswollen in fresh 30% H₂O/acetone for 4 d to remove the sol portion andthe copper catalyst. The resulting materials were colorless andtransparent.

Photodegradation of MNs and SEC of the Degradation Products

Irradiation of THF-swollen 3 with 350 nm light for 30 min yielded alight yellow liquid. After irradiation for two days to ensure completedegradation the THF solution was analyzed by SEC. As shown in FIG. 8, asexpected, the primary degradation product 4 (800) was a four arm starpolymer, with M_(n) equal to twice that of 2 (810), indicating that thepore size of the parent MN was defined by the length of 2. A smallamount of material having M_(n) equal to half that of 2 was alsoobserved (820), presumably arising from “dangling chains” (MACs thatonly reacted on one end) within the network. These remainingfunctionalities may be later utilized for decoration of the materialwith functional species. With reference to FIG. 9, the hypothesizedmolecular structure of 3 (900) and degradation product 4 (910) can beseen.

b. Star Polymer Macromonomer

General

Star Polymer Macromonomer 15 was prepared via a one-pot strategy. Theconditions for ATRP and CuAAC are essentially identical, with theimportant catalytic entity being Cu(I) in both cases. Therefore, aone-pot star polymer synthesis using a small, tetrafunctional azide wasused. With reference to FIG. 10, the initiator 13 (1010) has an alkyneseparated from the initiation site by an NBOC functionality, thusenabling cleavage of the resulting polymer from the alkyne. Treatment of13 (1010) with 0.25 equivalents of tetraazide 14 and 200 equivalents oftBA with CuBr catalyst, PMDETA ligand, and 50-50 toluene-DMF solventyielded star polymer 15 (1020) (M_(n)(SEC)=37,200, PDI=1.11), the resultof tandem CuAAC coupling and ATRP (Scheme 6). Conversion of the bromineend groups of 15 (1020) to azides by treatment with NaN₃ in DMF yieldedstar MAC 17 (1030) (Scheme 6), FIG. 11 shows the ¹H NMR resonances in 17corresponding to the triazole proton resulting from the CuAAC reaction,the methylene protons from 14 and 13, the aromatic protons of 13, theterminal protons adjacent to the azide groups, and the backbone andtert-butyl protons of ptBA. With reference to FIG. 12, comparison of theFTIR spectra of 15 and 17 confirms the existence of azide groups in 17.

Returning to FIG. 10, CuAAC crosslinking of 17 (1030) with bifunctionalalkyne 18 (1040) (under the same conditions used for the linear polymersdescribed above yielded insoluble gel materials 19 (1050).Photodegradation of 19 (1050) yielded linear polymer 20 (1060), withM_(n) approximately one-half that of MAC 17 (1030) as the primarydegradation product. Irradiation of the 90:10 THF:water swollen materialfor 25 minutes yielded a light yellow liquid and no visible trace of theinsoluble material. Continued irradiation for 2 d and SEC analysisyielded product 20 which possessed the expected M_(n) confirming thepresence of tetra-functional branching points in the parent MN. As forthe case with the linear MACs, there existed a low molecular weight SECpeak (˜10,000 Da) corresponding to unreacted arms of the star MACs.

Synthesis of2-nitro-3-(tertbutyldimethylsilyloxymethyl)-hydroxymethylbenzene(Compound 9)

To a clean, dry round-bottom flask was added2-nitro-1,3-benzenedimethanol (818 mg, 4.47 mmol), anhydrous DMF (40mL), and imidazole (304.2 mg, 4.47 mmol). The solution was maintained at0° C. while tert-butyldimethylsilylchloride (337 mg, 2.24 mmol) wasslowly added. The resulting pale yellow solution was allowed to warm toroom temperature and stirred overnight under argon before being dilutedwith ethyl acetate (100 mL), washed with water (5×50 mL), dried overMgSO₄, filtered, concentrated on a rotary evaporator, and purified bysilica gel chromatography (30% EtOAc:hexanes) to yield3-(tert-butyldimethylsilyloxymethyl)-2-nitro-hydroxymethylbenzene as ayellow oil which crystallized upon further solvent removal in vacuo. Theexcess 2-nitro-1,3-benzenedimethanol was recovered and re-subjected tothe reaction conditions to yield Compound 9 in 80% yield after threeiterations.

Synthesis of 3-(tert-butyldimethylsilyloxymethyl)-2-nitrobenzoic acid(Compound 10)

An aqueous solution of 15% NaHCO₃ (18 mL) was added to a stirringsolution of Compound 9 (1.80 g, 2.69 mmol) in acetone (60 mL) at 0° C.NaBr (133 mg, 1.29 mmol) and TEMPO (18.9 mg, 0.121 mmol) were then addedfollowed by the slow addition of trichloroisocyanuric acid (2.81 g, 12.1mmol). The resulting solution was allowed to warm to room temperatureand stirring for 1 d after which time 2-propanol (3.63 mL) was added.The mixture was filtered over Celite, concentrated on a rotaryevaporator, dissolved in 18 mL of saturated Na₂CO₃, washed with EtOAc(3×10 mL), acidified with 1 M HCl, and extracted with ethyl acetate(3×50 mL). The resulting organics were dried over Na₂SO₄, filtered,concentrated on a rotary evaporator and purified by silica gelchromatography (10% MeOH:CH₂Cl₂) to yield Compound 10 (1.05 g, 56%) as awhite solid.

Synthesis of3-(tert-butyldimethylsilyloxymethyl)-2-nitro-N-propargylbenzamide(Compound 10)

HBTU (183 mg, 0.482 mmol) and HOBt (65.1 mg, 0.482 mmol) were added to astirring solution of Compound 10 (150 mg, 0.482 mmol) in anhydrous DMF(4.82 mL) followed by N,N-diisopropylethylamine (187 mg, 1.45 mmol) andpropargyl amine (79.6 mg, 1.45 mmol). The resulting solution was stirredfor 30 h at room temperature after which time 25 mL of EtOAc were addedand the solution was washed with water (3×10 mL), aqueous saturatedNH₄Cl (1×10 mL), and brine (1×10 mL). The organic layer was dried overMgSO₄, filtered, and concentrated on a rotary evaporator. The resultingoil was purified by silica gel chromatography (50% EtOAc:hexanes) toyield Compound II as a white solid (92.3 mg, 55%).

Synthesis of 3-(2-bromoisobutyryl)methyl-2-nitro-N-propargylbenzamide(Compound 13)

TBAF (4.19 mL of a 1.0 M solution in THF) was added dropwise to astirring solution of Compound 11 (487 mg, 1.40 mmol) in THF (14 mL), TLCanalysis showed complete reaction after 5 minutes, after which time theTHF was removed on a rotary evaporator and the resulting oil wasdissolved in EtOAc (50 mL), washed with saturated NH₄Cl (2×20 mL), water(2×50 mL), dried over MgSO₄, concentrated in vacuo. The resulting whitesolid (Compound 12) was dissolved in anhydrous THF (14 mL),triethylamine (184 mg, 1.81 mmol) was added, and the resulting solutionwas added dropwise to a stirring solution of □-bromoisobutyrylbromide(225 mg, 1.82 mmol) in THF (5 mL) at 0° C. A white precipitate formedimmediately. The mixture was allowed to warm to room temperature andstirred overnight under argon atmosphere after which time the solidsalts were filtered, and the solvent was removed on a rotary evaporator.The resulting yellow oil was dissolved in ethyl acetate (50 mL) andwashed with water (3×20 mL), dried over MgSO₄, concentrated in vacuo,and purified by silica gel chromatography (50% EtOAc:hexanes) to yieldCompound 13 (321 mg, 60%) as a white solid.

Synthesis of 4-arm ptBA star polymer (15)

CuBr (115 mg, 0.80 mmol) was added to a clean, dry round bottom flaskwhich was evacuated for 5 minutes before backfilling with argon. Freshlydistilled tBA (10.3 g, 80.0 mmol) and a degassed solution of Compound 14(23.6 mg, 0.100 mmol) in toluene (2.50 mL) were added via a degassedsyringe. A solution of Compound 13 (151 mg, 0.400 mmol) in DMF (2.50 mL)was bubbled with argon for minutes and added to the reaction flask via adegassed syringe. The flask was immediately submerged in liquid N₂ untilfrozen, subjected to vacuum for 10 min, removed from liquid N₂ andbackfilled with argon. After completely thawing, the light greenreaction mixture was submerged in a preheated oil bath at 70° C. andstirred under argon atmosphere for 3.5 h. Samples were taken via adegassed syringe at various time intervals for kinetic analysis by ¹HNMR. When the reaction had reaction˜40% conversion, the flask was openedto air and submerged in liquid nitrogen to quench the reaction. Dilutionwith THF, passing through a neutral alumina column, concentration on arotary evaporator, and precipitation (3× in a 10:1 volume of 50-50methanol-water three times) yielded star polymer 15 as a white solid.

Synthesis of tetra-azido functionalized ptBA star polymer (MAC 17)

Star polymer MAC 17 was prepared in a manner similar to linear MAC 1using 4-arm ptBA star polymer 15 as the substrate as opposed to Compound4.

Synthesis of Bifunctional Alkyne Crosslinker (Compound 18)

Hexynoyl chloride (1.74 g, 13.3 mmol) was added dropwise to a stirringsolution of butane-1,4-diol (0.901 g, 10.2 mmol) and triethylamine (1.35g, 13.3 mmol) in methylene chloride (25 mL). A white precipitate formedimmediately. The mixture was stirred overnight at room temperature afterwhich time it was filtered and concentrated on a rotary evaporator. Theresidue was dissolved in EtOAc (50 mL) and washed with water (2×25 mL),saturated aqueous Na₂CO₃ (2×25 mL), and brine (1×25 mL). The organiclayer was dried over MgSO₄, filtered, concentrated on a rotaryevaporator, and purified by silica gel chromatography (80%hexanes:EtOAc) using anisaldehyde stain to yield Compound 18 as acolorless oil (2.00 g, 70%).

Preparation of Model Network 19

The MAC precursor 17 and CuBr (10 equiv. per azide) were added to aclean glass vial which was capped with a septum and evacuated for 5 minbefore backfilling with argon. Anhydrous DMF (30% by weight of MAC) wasadded via a degassed syringe, followed by crosslinker 18 (1 equiv. ofalkyne to azide), and PMDETA (20 equiv. per azide). The vial was placedin an ultrasonication bath for 10 s to homogenize the solution beforeplacing the vial in a preheated oven at 60° C. under argon for overnightreaction to yield insoluble MNs which were deep blue in color due to thepresence of trapped copper catalyst.

Photodegradation of Model Network 19

The insoluble MN materials were removed from the vials in which theywere prepared, and added to a larger vial containing fresh methylenechloride. For 2 d, the solvent was exchanged approximately every 10hours until the gel materials became colorless. After this time, themethylene chloride was removed and the MN was swollen in 90% THF:water.Excess THF:water was removed with a Pasteur pipette, and the vialcontaining the swollen material was capped tightly and placed in arayonet reactor under UV irradiation at 350 nm peak wavelength.

Samples were taken at various times for SEC analysis. Completedegradation of insoluble material was observed after 25 min, but SECanalysis indicated that several days were needed for completedegradation.

8. Example of Substitution of Bromine End Group with Hydroxyl Group

Bromo-terminated p(t-BMA)-b-p(St) with α-hydroxyl end group (Mn=5861,Mw/Mn=1.17, 0.4 g, 58 mmol) and 10 eq. of Na₂CO₃ (0.1 g) were placedinto 25 mL rbf and degassed and back-filled with argon three times.Degassed DMF (10 mL) was added using a syringe (white suspension—Na₂CO₃was partly dissolved). Then 30 eq. of 4-aminobutanol (300 ηL) was addeddrop-wise under argon. After stirring for 48 h at room temperature, theα,ω-hydroxyl terminated p(t-BMA)-b-p(St) block copolymer wasprecipitated into a 10-fold excess of a 50/50 v/v mixture of MeOH/D.I.water. ¹H NMR (CDCl₃): The peak of CH(Ph)—Br at δ=4.4-4.6 ppmdisappeared and a new peak of —CH₂—OH at δ=3.4-3.6 arised.

9. EXAMPLE OF SUBSTITUTION OF BROMINE END GROUP WITH ACRYLATE GROUP

Bromo-terminated p(t-BMA)-b-p(St) with α-hydroxyl end group istransformed into α,ω-hydroxyl-terminated p(t-BMA)-b-p(St) via theprocedure outlined in section 7 above. The product was added to a 100 mLrbf, sealed with a rubber septum, degassed and back-filled with argonthree times before dissolving in 20 mL of degassed THF. Then 11 molarexcess (with regard to the OH groups) of deoxygenated TEA (306 ηL, 2.24mmol) was added and the solution was cooled in an ice-bath. A 10 molarexcess of acryloyl chloride (162 ηL, 2.04 mmol) was introduced drop-wiseand white precipitation appeared. After stirring of the solution for 24h at room temperature, the resulting macromonomer was precipitated intoa 10-fold excess of a 50/50 v/v mixture of MeOH/D.I. water. ¹H NMR(CDCl₃): The peaks of —CH₂—OH protons (δ=3.8-3.9 ppm) and —CH₂—OCO—protons (δ=4.15-4.3 ppm) disappeared and new peaks of acrylate groupsraised: 2× CH₂=protons (δ=6.43 and 5.80 ppm), 2× —CH—COO— (δ=6.05 ppm),3× CH₂—OCO— (δ=4.27, 4.36, and 4.43 ppm) and CH(Ph)—NH proton δ=3.90ppm.

8. REFERENCES

-   i. Flory, P. J. Principles of Polymer Chemistry; Cornell Univ.    Press: Ithaca, N.Y., 1953; pp 432-493.-   ii. Osada, Y.; Ross-Murphy, S. B. Scientific American 1993, 268,    82-7.-   iii. Kafouris, D.; Themistou, E.; Patrickios, C. S, Chem. Mater.    2006, 18, 85-93.-   iv. Georgiou, T. K.; Patrickios, C. S. Macromolecules, 2006, 39,    1560-1568.-   v. Hild, G. Prog. Polym. Sci. 1998, 23, 1019-1149.-   vi. Hoffman, A. S. Adv. Drug Deliver Rev. 2002, 54, 3-12.-   vii. Rostovtsev, V. V.; Green, L. G.; Fokin, V, V.; Sharpless, K. B.    Angew. Chem., Int. Ed Engl. 2002, 41, 2596-2599.-   viii. Tornoe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,    67, 3057-3064.-   ix. Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int d.    Engl 2001, 40, 2004-2021.-   x. Calvo-Flores, F. G.; Isac-Garcia, J.; Hernandez-Mateo, F.;    Perez-Balderas, F.; Calvo-Asin, J. A.; Sanchez-Vaquero, E.;    Santoyo-Gonzalez, F., Org. Lett. 2000, 2, (16), 2499-2502.-   xi, Korostova, S. E.; Mikhaleva, A. I.; Shevchenko, S. G.;    Sobenina, L. N.; Fel'dman, V. D.; Shishov, N. I., Zhurnal Prikladnot    Khimii (Sankt-Peterburg, Russian Federation) 1990, 63, (1), 234-7.-   xii. Diaz, D. D.; Punna, S.; Holzer, P.; McPherson, A. K.;    Sharpless, K. B.; Fokin V. V.; Finn, M. G. J. Polym. Sci., Part A:    Polym. Chem. 2004, 42, 4392-4403-   xiii. Bochet, C. G., J. Chem. Soc., Perkin Trans. 12002, 125.

The invention claimed is:
 1. A method of preparing a linearmacromonomer, comprising: a) preparing an initiator with at least oneterminal halogen group, wherein the initiator contains a degradablelinker for each of the terminal halogen groups, the degradable linkerselected from the group consisting of a photodegradable linker, anozonolyzable linker, and a biodegradable linker; b) using the initiator,polymerizing a first monomer through ATRP to form a polymeric halidehaving at least one terminal halogen group; c) modifying the polymerichalide through a post-polymerization transformation to replace theterminal halogen groups with desired functional end groups, wherein thedesired functional end groups are selected from the group consisting ofhydroxyl, acrylate, and azide.
 2. The method of claim 1, wherein themonomer functionality is selected from the group consisting ofacrylates, methacrylates, styrenics, and polyacids.
 3. The method ofclaim 1, wherein the polymerization step is repeated using a secondmonomer.
 4. The method of claim 1, wherein the post-polymerizationtransformation to add an azide functional end group comprises treatingthe polymeric halide with sodium azide in dimethylformamide.
 5. Themethod of claim 1, wherein the post-polymerization transformation isconducted to add an azide functional end group, further comprising thestep of modifying the polymeric azide through CLICK chemistry to add afunctional end group selected from the group consisting of aldehyde,hydroxy, carboxy, amine, peptide, epoxide, and thiol.
 6. A linearmacromonomer, prepared by the method comprising: a) preparing aninitiator with at least one terminal halogen group, wherein theinitiator contains a degradable linker for each of the terminal halogengroups, the degradable linker selected from the group consisting of aphotodegradable linker, an ozonolyzable linker, and a biodegradablelinker; b) using the initiator, polymerizing a first monomer throughATRP to form a polymeric halide having at least one terminal halogengroup; c) modifying the polymeric halide through a post-polymerizationtransformation to replace the terminal halogen groups with desiredfunctional end groups, wherein the desired functional end groups areselected from the group consisting of hydroxyl, acrylate, and azide. 7.The linear macromonomer of claim 6, wherein the monomer functionality isselected from the group consisting of acrylates, methacrylates,styrenics, and polyacids.
 8. The linear macromonomer of claim 6, whereinthe polymerization step is repeated using a second monomer.
 9. Thelinear macromonomer of claim 6, wherein the post-polymerizationtransformation to add a desired azide functional end group comprisestreating the polymeric halide with sodium azide in dimethylformamide.10. The linear macromonomer of claim 6, wherein the post-polymerizationtransformation is conducted to add an azide functional end group,further comprising the step of modifying the polymeric azide throughCLICK chemistry to add a functional end group selected from the groupconsisting of aldehyde, hydroxy, carboxy, amine, peptide, epoxide, andthiol.